Coating for a medical device having an anti-thrombotic conjugate

ABSTRACT

An implantable device having a coating comprising a comb-type anti-thrombotic conjugate to prevent or reduce the formation of thrombosis on the surface of the device. The device includes a frame expandable from a first diameter to a second diameter wherein the frame has an inner surface and an outer surface, a plurality of structural features disposed along the frame and a plurality of polymer anti-thrombotic conjugate particles situated with the plurality of structural features. The particle can be created utilizing the comb type polymer and heparin conjugate as a carrier for a therapeutic agent within its polymer matrix. The structural features allow for particles having differing properties to be placed at various locations along the device. Moreover, particles having at least two different agents can be located within the same structural feature.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 11/741,997filed Apr. 30, 2007, which is incorporated herein by reference in itsentirety.

FIELD OF INVENTION

The present invention relates to a material for application to at leasta portion of the surface of an article or for implantation within anarticle. In particular, this invention relates to a comb typebioabsorbable polymer having an anti-thrombotic composition conjugatedtherewith wherein an anti-restenotic agent may be contained within thepolymer matrix of the bioabsorbable polymer. This invention also relatesto a device having the conjugate coated to its surface or containedwithin the device itself.

BACKGROUND OF INVENTION

Stenosis is the narrowing or constriction of a vessel resulting from thebuildup of fat, cholesterol, and other substances over time. In severecases, stenosis can completely occlude a vessel. Interventionalprocedures have been employed to open stenosed vessels. One example ofan interventional procedure is percutaneous transluminal coronaryangioplasty (PTCA) or balloon coronary angioplasty. In this procedure, aballoon catheter is inserted and expanded in the constricted portion ofthe vessel for clearing a blockage. About one-third of patients whoundergo PTCA suffer from restenosis, wherein the vessel becomes blockedagain, within about six months of the procedure. Thus, restenosedarteries may have to undergo another angioplasty. In order to avoidadditional PTCA implantable medical devices such as stents have beenplaced within the vessel following PTCA or in lieu of PTCA. Nonetheless,restenosis may still result even with the implantation of a stent.

Restenosis can be inhibited by a common procedure that consists ofinserting a stent into the effected region of the artery instead of, oralong with, angioplasty. A stent is a tube made of metal or plastic,which can have either solid walls or mesh walls. Most stents in use aremetallic and are either self-expanding or balloon-expandable. Thedecision to undergo a stent insertion procedure depends on certainfeatures of the arterial stenosis. These include the size of the arteryand the location of the stenosis. The function of the stent is tobuttress the artery that has recently been widened using angioplasty,or, if no angioplasty was used, the stent is used to prevent elasticrecoil of the artery. Stents are typically implanted via a catheter. Inthe case of a balloon-expandable stent, the stent is collapsed to asmall diameter and slid over a balloon catheter. The catheter is thenmaneuvered through the patient's vasculature to the site of the lesionor the area that was recently widened. Once in position, the stent isexpanded and locked in place. The stent stays in the artery permanently,holds it open, improves blood flow through the artery, and relievessymptoms (usually chest pain).

Stents are not completely effective in preventing restenosis at theimplant site. Restenosis can occur over the length of the stent and/orpast the ends of the stent. Physicians have recently employed new typesof stents that are coated with a thin polymer film loaded with a drugthat inhibits smooth cell proliferation. The coating is applied to thestent prior to insertion into the artery using methods well known in theart, such as a solvent evaporation technique. The solvent evaporationtechnique entails mixing the polymer and drug in a solvent. The solutioncomprising polymer, drug, and solvent can then be applied to the surfaceof the stent by either dipping or spraying. The stent is then subjectedto a drying process, during which the solvent is evaporated, and thepolymeric material, with the drug dispersed therein, forms a thin filmlayer on the stent.

The release mechanism of the drug from the polymeric materials dependson the nature of the polymeric material and the drug to be incorporated.The drug diffuses through the polymer to the polymer-fluid interface andthen into the fluid.

Release can also occur through degradation of the polymeric material.The degradation of the polymeric material may occur through hydrolysisor an enzymatic digestion process, leading to the release of theincorporated drug into the surrounding tissue.

An important consideration in using coated stents is the release rate ofthe drug from the coating. It is desirable that an effective therapeuticamount of the drug be released from the stent for a reasonably longperiod of time to cover the duration of the biological processesfollowing and an angioplasty procedure or the implantation of a stent.Burst release, a high release rate immediately following implantation,is undesirable and a persistent problem. While typically not harmful tothe patient, a burst release “wastes” the limited supply of the drug byreleasing several times the effective amount required and shortens theduration of the release period. Several techniques have been developedin an attempt to reduce burst release. For example, U.S. Pat. No.6,258,121 B1 to Yang et al. discloses a method of altering the releaserate by blending two polymers with differing release rates andincorporating them into a single layer.

A potential drawback associated with the implantation of a drug elutingstent (DES) is that thrombosis may occur at different times followingimplantation or deployment. Thrombosis is the formation of blood clotson or near an implanted device in the blood vessel. The clot is usuallyformed by an aggregation of blood factors, primarily platelets andfibrin, with entrapment of cellular elements. Thrombosis, like stenosis,frequently causes vascular obstruction at the point of its formation.Both restenosis and thrombosis are two serious and potentially fatalconditions that require medical intervention. A thrombus formation onthe surface of a stent is frequently lethal, leading to a high mortalityrate of between 20 to 40% in the patients suffering from a thrombosis ina vessel.

Although effective in reducing restenosis, some of the components of thecoatings utilized to prevent restenosis may increase the risk ofthrombosis. Drug eluting stents are typically not associated with anincrease of acute and subacute thrombosis (SAT), or a medium termthrombosis (30 days after stent implantation) following a stentimplantation. Long term clinical follow up studies, however, suggestthat these devices may be involved with increased incident rates of verylong term thrombosis (LST). Although the increase of LST has been foundto be less than 1%, a high mortality rate is usually associated withLST. One way to prevent this is to include a coating of ananti-coagulant, such as heparin, on the device.

One way to address the formation of stent thrombosis is through the useof a anticoagulant such as a heparin. Heparin is a substance that iswell known for its anticoagulation ability. It is known in the art toapply a thin polymer coating loaded with heparin onto the surface of astent using the solvent evaporation technique. For example, U.S. Pat.No. 5,837,313 to Ding et al. describes a method of preparing a heparincoating composition, A drawback to the use of heparin, however is thatit does not co-exist well with agents that prevent restenosis. Forexample, if heparin is mixed with an anti-thrombotic agent within apolymer coating, the hydrophilic nature of heparin will interfere withthe desired elution profile for the anti-restenotic agent. For example,therapeutic agent is embedded in the matrix of a polymer coating bysolvent processing. If an anti-coagulant is also embedded in the polymermatrix, it will attract water in an uncontrolled manner. This can happenduring manufacturing or when the coated device is implanted and willadversely affect the stability or efficacy of the agent and/or interferewith the desired elution profile.

Nonetheless, several approaches have been proposed for combininganti-thrombotic and therapeutic agents within the coatings for animplantable medical device. U.S. Pat. No. 5,525,348—Whitbourne disclosesa method of complexing pharmaceutical agents (including heparin) withquarternary ammonium components or other ionic surfactants and boundwith water insoluble polymers as an antithrombotic coating composition.This method suffers from the possibility of introducing naturallyderived polymer such as cellulose, or a derivative thereof, which isheterogeneous in nature and may cause unwanted inflammatory reactions atthe implantation site. These ionic complexes between an antithromboticagent such as heparin and an oppositely charged carrier polymer may alsonegatively affect the coating integration, and if additionalpharmaceutical agents are present, may affect the shelf stability andrelease kinetics of these pharmaceutical agents.

A slightly different approach is disclosed in U.S. Pat. Nos. 6,702,850,6,245,753, and 7,129,224—Byun wherein antithrombotic agents, such asheparin, are covalently conjugated to a non-absorbable polymer, such asa polyarylic acid, before use in a coating formulation. The overallhydrophobicity of these conjugates is further adjusted by addition of ahydrophobic agent such as octadecylamine, which is an amine with a longhydrocarbon chain. This approach has several potential disadvantagessuch as the known toxicity of polyacrylic acid after heparin ismetabolized in vivo. The addition of a hydrophobic amine also raises theconcern of tissue compatibility and reproduction of the substitutionreactions of each step. Moreover, the remaining components of thecoating are not biodegradable.

Another antithrombotic coating approach is disclosed in U.S. Pat. Nos.6,559,132—Holmer, 6,461,665—Scholander, and 6,767,405—Eketrop whereby acarrier molecule such as chitosan is conjugated to an activated metalsurface of a medical device. Thereafter, heparin is covalentlyconjugated to an intermediate molecule. This process may be repeatedseveral times until a desired antithrombotic layer is achieved.Alternatively, this coating can be achieved in a batch process mode.This approach, however, is not readily applicable to a medical devicethat is coated with a polymer coating that contains pharmaceuticalagent/s. Some of these successful anti-restenotic agents such assirolimus may be damaged during these conjugating processes, especiallythese processes where aqueous processes are involved.

PCT application WO2005/097223 A1—Stucke et al, discloses a methodwherein a mixture of heparin conjugated with photoactive crosslinkerswith dissolved or dispersed with other durabal polymers such asPoly(butyl methacrylate) and poly(vinyl pyrrolidone) in a same coatingsolution and crosslinked with UV light in the solution or after thecoating is applied. The potential disadvantage of this approach is thatthe incorporated drug/s may be adversely affected by the high energy UVlight during crosslinking process, or worse, the drug/s may becrosslinked to the matrix polymers if they possess functional groupsthat may be activated by the UV energy.

Another general approach as disclosed in US 2005/0191333 A1, US2006/0204533 A1, and WO 2006/099514 A2,—all by Hsu, Li-Chien, et al.,uses a low molecular weight complex of heparin and a counter ion(stearylkonium heparin), or a high molecular weight polyelectrolytecomplex, such as dextran, pectin to form a complex form of anantithrombotic entity. These antithrombotic complexes are furtherdispersed in a polymer matrix that may further comprise a drug. Suchapproaches create a heterogeneous matrix of a drug and a hydrophilicspecies of heparin wherein the hydrophilic species attract water beforeand after the implantation to adverse the stability and release kineticsof the drug. In addition, the desired antithrombotic functions ofheparin and similar agent should be preferably located on the surface,not being eluted away from the surface of a coated medical device.

Thus, there remains a need for a coating material that can satisfy thestringent requirements, as described above, for applying on at least onesurface of a medical device and can be prepared through a process thatis compatible with the sensitive pharmaceutical or therapeutic agentsimpregnated in the coatings. This helps to fill a need for a coatingthat treats both restenosis and prevents thrombosis when applied to theouter surface of a drug eluting stent.

SUMMARY OF THE INVENTION

A conjugate between a heparin and a comb type bioabsorbable polymer witha free carboxyl end group and a device having the conjugate applied toits surface or embedded within its structure is provided. The outmostlayer of the coating comprises the conjugate of the present invention,which prevents the formation of thrombosis, and also serves to modulatethe release kinetics of the agent(s) contained within an inner layer(s)of the coating.

A first or sub-layer of the coating is prepared by mixing a polymericmaterial and a biologically active agent with a solvent, thereby forminga homogeneous solution. The polymeric material can be selected from awide range of synthetic materials, but in one exemplary embodiment, apoly(lactide-to-glycolide) (PLGA) is used. The biologically active agentis selected depending on the desired therapeutic results. For example,an antiproliferative drug such as paclitaxel, an immunosuppressant, suchas a rapamycin, and/or anti-inflammatory drug, such as dexamethasone,may be included in the inner layer. Once prepared, the solution can beapplied to the device through a dipping or spraying process. Duringdrying, the solvent evaporates, and a thin layer of the polymericmaterial loaded with the biologically active agent is left coated overthe stent. It should be noted that the current invention is not limitedto just one inner layer or biologically active agent per layer. It iswithin the scope of this invention to add one or more distinctbiologically active agents to each layer and/or have more than one innerlayer loaded with a biologically active agent.

The second or outer layer comprises an anti-thromboticheparin-bioabsorbable polymer conjugate. This coating may be appliedover the inner drug-containing layers using, for example, a dip coatingor spray coating process. In one exemplary embodiment of the presentinvention, the outer layer comprising an anti-thromboticheparin-bioabsorbable polymer conjugate that may be dissolved in a mixedsolvent system comprising ethyl acetate (EA) and isopropanol (IPA). Thesolution is then sprayed onto the surface of the device that has alreadybeen coated with the agent-containing layer as described above. Afterdrying, the anti-thrombotic heparin bioabsorbable polymer conjugateremains in the outer layer of the coating, allowing agent from the innerlayer to be eluted there through.

The coated device is inserted into an afflicted area of a body, forexample, a vessel like the coronary artery, using an appropriateprocedure that depends on the properties of the device. Once in place,the device will hold the vessel open. The biologically active agent willbe released from the first layer, thereby providing the desiredtherapeutic result, such as inhibiting smooth cell proliferation. Theanti-thrombotic heparin-bioabsorbable polymer conjugate in the outmostlayer becomes partially hydrated and prevents blood coagulation on andaround the device, thus inhibiting thrombosis and sub-acute devicethrombosis. In addition, the anti-thrombotic heparin-bioabsorbablepolymer conjugate in the outmost layer may additionally reduce orprevent the burst release of the biologically active agent from theinner drug containing layer, thereby allowing the release to occur overa relatively extended period of time.

Alternatively, a particle can be created utilizing the comb type polymerand heparin conjugate as a carrier for a therapeutic agent within itspolymer matrix. In this embodiment the agent is somewhat associated withthe hydrophobic core of the comb polymer. The agent is co-dissolved withthe conjugate using a solvent that is later evaporated creatingparticles with the agent at their core. These particles are ideallysuited for placement within the structure of a device. For example, adevice may have structural features such as wells, indentations, folds,or channels having particles therein. This allows for particles havingdiffering properties to be placed at various locations along the device.Moreover, particles having at least two different agents can be locatedwithin the same structural feature. Agent is released from thestructural feature as the particles degrade. Simultaneously, thepresence of heparin will prevent thrombosis at the placement site of thedevice.

DESCRIPTION OF THE DRAWINGS

The features and advantages of the invention will be apparent to thoseof ordinary skill in the art from the following detailed description ofwhich:

FIG. 1 is a schematic representation of a ring opening polymerization ofa lactone dimer (lactide) with polyvinyl alcohol (PVA) as the initiatorthat forms a comb type polymer.

FIG. 2 is a schematic representation of the conjugation of heparin toPVA-initiated PLA comb type biodegradable polymer.

FIG. 3 is a schematic of a coating having the biodegradable comb typepolyester heparin conjugate of the present invention present in an outerlayer applied to the surface of a device.

FIG. 4 is a schematic view showing a biodegradable comb type polyesterheparin conjugate of the present invention first combined with a drug toform nanoparticles or microspheres.

FIG. 5 is an isometric view of an expandable medical device withparticles selectively placed into structural features of the device.

FIG. 6 is a cross sectional view of an expandable medical device havingparticles in accordance with the present invention in a first pluralityof holes.

DETAILED DESCRIPTION OF THE INVENTION

One or more layers of polymeric compositions are applied to a medicaldevice to provide a coating thereto or are loaded within a structuralfeature of the medical device. The polymeric compositions performdiffering functions. For example, one layer may comprise a base coatthat allows additional layers to adhere thereto. An additional layer(s)can carry bioactive agents within their polymer matrices. Alternatively,a single coat may be applied wherein the polymeric composition is suchthat the coat performs multiple functions, such as allowing the coatingto adhere to the device and housing an agent that prevents thrombosis.Other functions include housing an agent to prevent restenosis.

The chemical nature of an agent can limit the number of agents that acoating may carry. For example, an antithrombotic agent tends to behydrophilic while an anti-proliferative agent tends to be comparativelyhydrophobic. Hence, it is desired to entrap a hydrophobic agent withinthe matrix of a polymer coating to limit its exposure to water andcontrol its elution from the matrix. The present invention supports twoagents having differing properties in close proximity by providing aconjugate between an anti-coagulant such as heparin and a bioabsorbablepolymer with a free carboxyl end group. This configuration will resultin the hydrophilic heparin agent being oriented substantially away fromthe hydrophobic agent that resides within the polymer matrix. Thus, whenapplied to a medical device the coating having the conjugate ensuresthat the anti-thrombotic agent is substantially oriented away from anyhydrophobic agents that may be contained within the polymer matrix.

The following definitions are provided for ease of understanding thepresent invention and should not be construed as limiting thedescription of then invention in any way.

As used herein, “stent” means a generally tubular structure constructedfrom any biocompatible material that is inserted into a conduit to keepthe lumen open and prevent closure due to a stricture or externalcompression.

As used herein, “biologically active agent” means a drug or othersubstance that has therapeutic value to a living organism includingwithout limitation antithrombotics, anticancer agents, anticoagulants,antiplatelet agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit restenosis, smooth muscle cellinhibitors, antibiotics, and the like, and/or mixtures thereof and/orany substance that may assist another substance in performing thefunction of providing therapeutic value to a living organism.

Exemplary anticancer drugs include acivicin, aclarubicin, acodazole,acronycine, adozelesin, alanosine, aldesleukin, allopurinol sodium,altretamine, aminoglutethimide, amonafide, ampligen, amsacrine,androgens, anguidine, aphidicolin glycinate, asaley, asparaginase,5-azacitidine, azathioprine, Bacillus calmette-guerin (BCG), Baker'sAntifol (soluble), beta-2′-deoxythioguanosine, bisantrene hcl, bleomycinsulfate, busulfan, buthionine sulfoximine, ceracemide, carbetimer,carboplatin, carmustine, chlorambucil, chloroquinoxaline-sulfonamide,chlorozotocin, chromomycin A3, cisplatin, cladribine, corticosteroids,Corynebacterium parvum, CPT-11, crisnatol, cyclocytidine,cyclophosphamide, cytarabine, cytembena, dabis maleate, dacarbazine,dactinomycin, daunorubicin HCl, deazauridine, dexrazoxane,dianhydrogalactitol, diaziquone, dibromodulcitol, didemnin B,diethyldithiocarbamate, diglycoaldehyde, dihydro-5-azacytidine,doxorubicin, echinomycin, edatrexate, edelfosine, eflomithine, Elliott'ssolution, elsamitrucin, epirubicin, esorubicin, estramustine phosphate,estrogens, etanidazole, ethiofos, etoposide, fadrazole, fazarabine,fenretinide, filgrastim, finasteride, flavone acetic acid, floxuridine,fludarabine phosphate, 5-fluorouracil, Fluosol®, flutamide, galliumnitrate, gemcitabine, goserelin acetate, hepsulfam, hexamethylenebisacetamide, homoharringtonine, hydrazine sulfate,4-hydroxyandrostenedione, hydrozyurea, idarubicin HCl, ifosfamide,interferon alfa, interferon beta, interferon gamma, interleukin-1 alphaand beta, interleukin-3, interleukin-4, interleukin-6,4-ipomeanol,iproplatin, isotretinoin, leucovorin calcium, leuprolide acetate,levamisole, liposomal daunorubicin, liposome encapsulated doxorubicin,lomustine, lonidamine, maytansine, mechlorethamine hydrochloride,melphalan, menogaril, merbarone, 6-mercaptopurine, mesna, methanolextraction residue of Bacillus calmette-guerin, methotrexate,N-methylformamide, mifepristone, mitoguazone, mitomycin-C, mitotane,mitoxantrone hydrochloride, monocyte/macrophage colony-stimulatingfactor, nabilone, nafoxidine, neocarzinostatin, octreotide acetate,ormaplatin, oxaliplatin, paclitaxel, pala, pentostatin, piperazinedione,pipobroman, pirarubicin, piritrexim, piroxantrone hydrochloride,PIXY-321, plicamycin, porfimer sodium, prednimustine, procarbazine,progestins, pyrazofurin, razoxane, sargramostim, semustine,spirogermanium, spiromustine, streptonigrin, streptozocin, sulofenur,suramin sodium, tamoxifen, taxotere, tegafur, teniposide,terephthalamidine, teroxirone, thioguanine, thiotepa, thymidineinjection, tiazofurin, topotecan, toremifene, tretinoin, trifluoperazinehydrochloride, trifluridine, trimetrexate, tumor necrosis factor, uracilmustard, vinblastine sulfate, vincristine sulfate, vindesine,vinorelbine, vinzolidine, Yoshi 864, zorubicin, and mixtures thereof.

Exemplary antiinflammatory drugs include classic non-steroidalanti-inflammatory drugs (NSAIDS), such as aspirin, diclofenac,indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen,piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid,fenoprofen, nambumetone (relafen), acetaminophen (Tylenol®), andmixtures thereof; COX-2 inhibitors, such as nimesulide, NS-398,flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxibsodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780,L-761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof;glucocorticoids, such as hydrocortisone, cortisone, prednisone,prednisolone, methylprednisolone, meprednisone, triamcinolone,paramethasone, fluprednisolone, betamethasone, dexamethasone,fludrocortisone, desoxycorticosterone, and mixtures thereof; andmixtures thereof.

As used herein, “effective amount” means an amount of pharmacologicallyactive agent that is nontoxic but sufficient to provide the desiredlocal or systemic effect and performance at a reasonable benefit/riskratio attending any medical treatment.

FIG. 3 illustrates an exemplary embodiment of a coating(s) of thepresent invention applied a surface 2. The surface 2 is located on, forexample, an implantable medical device. The coating comprises a first orinner layer 4 of polymeric film loaded with a biologically active agentthat, for example, prevents smooth cell proliferation and migration.First layer or coating 4 may contain more than one biologically activeagent.

One manner in which the agent is placed within the matrix of the polymerinvolves using a solvent or mixture of solvents whereby the agent andpolymer are dissolved therein. As the mixture dries, the solvent isremoved leaving the agent entrapped within the matrix of the polymer.Exemplary polymers that can be used for making the inner/first polymericlayer include polyurethanes, polyethylene terephthalate (PET),PLLA-poly-glycolic acid (PGA) copolymer (PLGA), polycaprolactone (PCL)poly-(hydroxybutyrate/hydroxyvalerate) copolymer (PHBV),poly(vinylpyrrolidone) (PVP), polytetrafluoroethylene (PTFE, Teflon®),poly(2-hydroxyethylmethacrylate) (poly-HEMA), poly(etherurethane urea),silicones, acrylics, epoxides, polyesters, urethanes, parlenes,polyphosphazene polymers, fluoropolymers, polyamides, polyolefins, andmixtures thereof. Exemplary bioabsorbable polymers that can be used formaking the inner/first polymeric film include polycaprolactone (PCL),poly-D, L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA),poly(hydroxybutyrate), polydioxanone, polyorthoester, polyanhydride,poly(glycolic acid), polyphosphoester, poly (amino acids),poly(trimethylene carbonate), poly(iminocarbonate), polyalkyleneoxalates, polyphosphazenes, and aliphatic polycarbonates.

A second or outmost layer 6 may comprise an anti-thromboticheparin-bioabsorbable polymer conjugate with strong anticoagulationproperties. The second layer of anti-thrombotic heparin-bioabsorbablepolymer conjugate may additionally have the effect of preventing a burstrelease of the biologically active agent dispersed in the first or inner4 layer, resulting in a relatively longer release period of the layer 4may contain more than one biologically active agent. In addition, theconjugate 6 orients the hydrophilic heparin 8 substantially away fromthe hydrophobic inner layer 4.

For purposes of illustrating the present invention, the coating(s) areapplied to a medical device such as stents and/or stent-graft. Ingeneral, stents are made from metal such as those manufactured fromstainless steel or cobalt chromium alloys. Stents may, however, also bemanufactured from polymeric materials. It is also to be understood thatany substrate, medical device, or part thereof having contact withorganic fluid, or the like, may also be coated with the presentinvention. For example, other devices such as vena cava filters andanastomosis devices may be used with coatings having agents therein orthe devices themselves may be fabricated with polymeric materials thathave the drugs contained therein. Any of the stents or other medicaldevices described herein may be utilized for local or regional drugdelivery. Balloon expandable stents may be utilized in any number ofvessels or conduits, and are particularly well suited for use incoronary arteries. Self-expanding stents, on the other hand, areparticularly well suited for use in vessels where crush recovery is acritical factor, for example, in the carotid artery.

It is desirable, but not required, that the first 4 and second 6coatings or layers cover at least a portion of the entire stent surface2. The application of the first layer 4 is accomplished through asolvent evaporation process or some other known method such as solventcast spray coating. The solvent evaporation process entails combiningthe polymeric material and the biologically active agent with a solvent,such as tetrahydrofuran (THF), which are then stirred to form a mixture.An illustrative polymeric material of the first layer comprisespolyurethane and an illustrative biologically active agent comprises arapamycin. The mixture is applied to the surface 2 of the stent byeither spraying the solution onto the stent; or dipping the stent intothe solution. After the mixture has been applied, the stent is subjectedto a drying process, during which, the solvent evaporates and thepolymeric material and biologically active agent form a thin film on thestent. Alternatively, a plurality of biologically active agents can beadded to the first layer 4.

The second or outmost layer 6 of the stent coating comprises ananti-thrombotic heparin-bioabsorbable polymer conjugate. Theanti-thrombotic heparin-bioabsorbable polymer conjugate may be solublein organic solvents or mixtures of organic solvents of varying polarity.The heparin 8 may comprise an unfracationated heparin, fractionatedheparin, a low molecular weight heparin, a desulfated heparin andheparins of various mammalian sources. Exemplary anti-thrombotic agentsmay include: Vitamin K antagonist such as Acenocoumarol, Clorindione,Dicumarol (Dicoumarol), Diphenadione, Ethyl biscoumacetate,Phenprocoumon, Phenindione, Tioclomarol, Warfarin; Heparin groupanti-platelet aggregation inhibitors such as Antithrombin III,Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Heparin, Nadroparin,Parnaparin, Reviparin, Sulodexide, Tinzaparin; other plateletaggregation inhibitors such as Abciximab, Acetylsalicylic acid(Aspirin), Aloxiprin, Beraprost, Ditazole, Carbasalate calcium,Cloricromen, Clopidogrel, Dipyridamole, Eptifibatide, Indobufen,Iloprost, Picotamide, Prasugrel, Prostacyclin, Ticlopidine, Tirofiban,Treprostinil, Triflusal; enzymatic anticoagulants such as Alteplase,Ancrod, Anistreplase, Brinase, Drotrecogin alfa, Fibrinolysin, ProteinC, Reteplase, Saruplase, Streptokinase, Tenecteplase, Urokinase; directthrombin inhibitors such as Argatroban, Bivalirudin, Dabigatran,Desirudin, Hirudin, Lepirudin, Melagatran, Ximelagatran; and otherantithrombotics such as Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, Rivaroxaban.

As shown in FIGS. 1 and 2, an exemplary anti-thromboticheparin-biocompatible copolymer conjugate is prepared as follows. First,as shown in FIG. 1, a cyclic dimer of d,l-lactide, is polymerized atelevated temperature of about 140 C, in the presence of a catalystStannous Octoate (Sn(Oct)₂ and a predetermined amount of poly(vinylalcohol) (PVA, sufficiently hydrolyzed to be water soluble) as the ringopening initiator. Ring opening polymerization results in an end productthat contains a homopolymer of polyester with hydroxyl end groups. Themolecular weight of each polymer is determined by the ratio between thecyclic dimer and the PVA initiator. The higher the ratio between thecyclic dimer to the initiator, the higher the molecular weight of thecopolymer of PVA-PLA.

In one embodiment of the present invention the hydroxyl groups at oneend of the final PVA-PLA copolymer may be further converted to acarboxyl group that may be employed in the subsequent conjugationreaction with a heparin molecule. Although any heparin molecule, arecombinant heparin, heparin derivatives or heparin analogues (having apreferred weight of 1,000-1,000,000 daltons) may be used in the couplingreaction to make the final anti-thrombotic heparin-bioabsorbable polymerconjugate, it is preferred to use a desulfated heparin to increase thecoupling efficiency of the reaction.

Once the anti-thrombotic heparin-bioabsorbable polymer conjugate isprepared, the second layer comprising the anti-thrombotic heparinbiocompatible copolymer conjugate may be applied directly over the firstlayer using the solvent evaporation method or other appropriate method.After the solvent is evaporate from the surface of an implantablemedical device, a thin film of comprising anti-thromboticheparin-bioabsorbable polymer conjugate is formed on the outmost surfaceof the device. Alternatively the comb-type anti-thrombotic biocompatiblecopolymer may be processed into microsphere or nanosphere forms thatalso contain a drug before added to a drug eluting medical device.

The following examples illustrate the creation of the conjugate and usesin accordance with the principle of the present invention.

I. Example 1 Preparation of a Comb-Type Biodegradable PLA Via a RingOpening Polymerization of a Lactone Dimers (Lactide) with Poly(VinylAlcohol, PVA) as the Initiator

As shown in FIG. 1, a pre-determined amount of d,l-lactide (from Purac,USA) is transferred to a dried round bottom glass reactor equipped witha magnetic stir bar. A pre-determined amount of poly(vinyl alcohol),(e.g. fully hydrolyzed Elvanol 70-03 from Du Pont, Inc.) and StannousOctoate (Sigma, St. Louis, USA) are added to the glass reactor. Theglass reactor is then sealed with a stopper and cycled three timesbetween an argon gas and vacuum to remove the air and oxygen inside thereactor. The sealed reactor is then gradually heated to 140 C. undervacuum and kept stirred with the magnetic stir bar. Upon completion ofthe reaction, the polymer is dissolved in methylene chloride andprecipitated in methanol and dried under vacuum and low heat.

II. Example 2 Preparation of Comb-Type Anti-ThromboticHeparin-Bioabsorbable Polymer Conjugate

As shown in FIG. 2, a comb-type PLA, such as created in accordance withExample 1 above, is dissolved in anhydrous dimethylformamide (DMF),followed by dissolution of succinic anhydride anddicyclohexylcarbodiimide (DCC). The resulting solution is kept for 5hours at room temperature under vacuum. The byproduct, dicyclohexylurea(DCU), and unreacted DCC and NHS are removed by filtration. Theresultant intermediate is then re-precipitated in methanol and dried invacuum oven. The carboxylic acid end caped intermediate is thenactivated by addition of N-hydroxylsuccinimide (NHS) indimethylformamide and further reacted with heparin for 4 hours at roomtemperature to make the final comb type conjugate of comb typebiodegradable polymer-heparin conjugate of the present invention. Thefinal conjugate is precipitated and freeze-dried.

III. Example 3 Coating of a Drug Eluting Stent with an Outmost LayerComprising a Comb-Type Absorbable Polymer-Heparin Conjugate

As shown in FIG. 3, the surface 10 of a cobalt chromium stent is spraycoated with a drug containing polymeric solution, which may comprise forexample, ethyl acetate (EA) containing PLGA and rapamycin. The weightratio between PLGA and rapamycin is 2:1. After the drug-containing layer20 is dried, a coating solution containing a comb-type absorbablepolymer-heparin conjugate is spray coated onto the first drug-containinglayer 20. After the layer is dried, a thin film 30 containing thecomb-type absorbable polymer-heparin conjugate is formed on the outmostsurface.

Coatings such as those described above can be thin, typically 5 to 8microns deep. The surface area of a device such as a stent, bycomparison is very large, so that the entire volume of the beneficialagent has a very short diffusion path to discharge into the surroundingtissue. The resulting cumulative drug release profile is characterizedby a large initial burst, followed by a rapid approach to an asymptote,rather than the desired “uniform, prolonged release,” or linear release.It is often desired to vary the elution pattern of a therapeutic agentfrom a device such as a stent. In addition, it is also desired to varythe amount of agent at different locations along the device. This can beaccomplished by placing an agent within a structural feature of thedevice.

As shown in FIG. 5, an expandable device has a plurality of structuralfeatures that facilitate the placement of at least one agent on thedevice. The expandable medical device 10 illustrated in FIG. 5 may becut from a tube of material to form a cylindrical expandable device. Theexpandable medical device 10 includes a plurality of cylindricalsections 12 interconnected by a plurality of bridging elements 14. Thebridging elements 14 allow the device to bend axially when passingthrough the torturous path of vasculature to a deployment site and allowthe device to bend axially when necessary to match the curvature of alumen. A network of elongated struts 18 that are interconnected byductile hinges 20 and circumferential struts 22 comprise the cylindricaltubes 12. During expansion of the medical device 10 the ductile hinges20 deform while the struts 18 are not deformed. Further details of anexample of the expandable medical device are described in U.S. Pat. No.6,241,762 incorporated herein by reference in its entirety.

The elongated struts 18 and circumferential struts 22 include structuralfeatures such as openings 30, some of which are selectively filled withan agent for delivery to the lumen in which the expandable medicaldevice is implanted. The depth of the openings 30 is dictated by thethickness of the struts 22. Other structural features may include raisedsections or dimples, slits, elongated openings, added material and anyfeature that can capture or contain a material that is desired to beplaced on the expandable device. In addition, other portions of thedevice 10, such as the bridging elements 14, may include structuralfeatures. In the particular example shown in FIG. 5, the openings 30 areprovided in non-deforming portions of the device 10, such as the struts18, so that the openings are non-deforming and the agent is deliveredwithout risk of being fractured, expelled, or otherwise damaged duringexpansion of the device. A further description of one example of themanner in which the beneficial agent may be loaded within the openings30 is described in U.S. Pat. No. 6,764,507 incorporated herein byreference in its entirety. In order to facilitate the placement of anagent or multiple agents within a structural feature of a device asshown in FIG. 5, a particle 40 can be created utilizing the comb typepolymer and heparin conjugate as a carrier for the therapeutic agent asshown in FIG. 4. In this embodiment the agent 42 is somewhat associatedwith the hydrophobic core 46 of the comb polymer 44. The agent 42 isco-dissolved with the conjugate using a solvent that is later evaporatedcreating particles with the agent at their core. These particles areideally suited for placement within the structure of a device such asillustrated in FIG. 5. For example, a device may have structuralfeatures such as wells, indentations, folds, or channels havingparticles therein. This allows for particles having differing propertiesto be placed at various locations along the device. Moreover, particleshaving at least two different agents can be located within the samestructural feature. Agent is released from the structural feature as theparticles degrade. Simultaneously, the presence of heparin will preventthrombosis at the placement site of the device.

FIG. 6 illustrates a cross sectional view of an opening 50 in the device10 of FIG. 5. A plurality of particles 40 is placed between two layers52 and 54. Layers 52 and 54 can be varied in composition and thicknessto control the exposure of particles 40 to an aqueous environment. Thiswill control the release of agent from within the core of the particles40. Additionally, the particles can be blended within a single materialand placed within opening 50 of device 10.

Examples of methods for the formation of nanoparticles andmicroparticles for placement on or within a structural feature of adevice are given below.

IV. Example 4 Formation of Nanoparticles Using a Comb-Type AbsorbablePolymer-Heparin and Paclitaxel

Twenty mg of Paclitaxel and 200 mg of poly(lactide-to-glycolide),PLGA50/50, are dissolved 16 ml of methylene chloride with gentlestirring. The formed solution is transferred to 250 ml of aqueoussolution containing 4% of (polyvinyl alcohol) (PVA) as an emulsifier.The combined solution is sonicated with an energy output of 50 mW in apulsed mode of a sonicator for 90 seconds. The emulsion is then stirredovernight at room temperature to remove the solvent. This formsnanospheres containing paclitaxel that are collected by centrifugationat 12000 rpm for 30 min and further washed with deionized water 4 timesto remove excess emulsifiers. The product is then freeze-dried beforeapplication.

V. Example 5 Formation of Microparticles Using a Comb-Type AbsorbablePolymer-Heparin and Paclitaxel

Twenty mg of Paclitaxel and 200 mg of poly(lactide-to-glycolide),PLGA50/50, are dissolved 16 ml of ethyl acetate (EA) with gentlestirring. Eighty ml of water (water for injection grade) is heated up to50 C and kept stirred by a magnetic stirring plate. A predeterminedamount of emulsifier (PVA, 0.4 g) is added to form an aqueous solution.The solution is then cooled to room temperature under constant stirring.Ethyl acetate (3.2 ml) is added to the aqueous solution under gentlestirring. Paclitaxel and PLGA solution is then slowly poured to theemulsified aqueous solution that is being stirred at 500 rpm. Theemulsion is further stirred for 4 hours at room temperature to solidifythe microspheres. The final microspheres are then collected byfiltration and washed 2 times with WFI water. The final microspheres arefreeze-dried over night before subsequent use.

FIG. 4 shows particles made in accordance with the above-examples placedwithin an opening of the device shown in FIG. 5. The particles may beplaced within these openings by a dry powder deposition method such asan electrostatic deposition process. These particle containing devicemay be further process to modulate the release kinetics of the drug witha process such as a solvent spray process to further modulate therelease kinetics the opening may also be covered by additional coveringsto adjust the release kinetics of the drug.

Although the present invention has been described above with respect toparticular preferred embodiments, it will be apparent to those skilledin the art that numerous modifications and variations can be made tothese designs without departing from the spirit or essential attributesof the present invention. Accordingly, reference should be made to theappended claims, rather than to the foregoing specification, asindicating the scope of the invention. The descriptions provided are forillustrative purposes and are not intended to limit the invention norare they intended in any way to restrict the scope, field of use orconstitute any manifest words of exclusion.

What is claimed is:
 1. An apparatus comprising: a frame expandable froma first diameter to a second diameter wherein the frame has an innersurface and an outer surface, the distance between the surfaces definingthe wall thickness of the frame; a plurality of structural featuresdisposed along the frame; and a plurality of polymer anti-thromboticconjugate particles situated with the plurality of structural features,wherein the anti-thrombotic conjugate comprises a biocompatible,bioabsorbable, hydrophobic polymer backbone having hydrophilic,antithrombotic end groups configured as an amphiphilic structure, thematerial having the following structure:

wherein n is an integer of 2-1000; and m is an integer of 100 to 5000;LA is repeating unit of lactic acid; SA is succinic acid; Hp isunmodified heparin conjugated to the material, the lactic acid, thesuccinic acid and the unmodified heparin form an integral part of theamphiphilic material the overall structure being-comb like in shape. 2.The apparatus of claim 1 wherein the plurality of structural featurescomprise ridges disposed on the surface of the frame.
 3. The apparatusof claim 1 wherein the plurality of structural features comprises aplurality of wells formed in the frame.
 4. The apparatus of claim 3wherein the wells extend from the outer surface to the inner surface. 5.The apparatus of claim 3 wherein the plurality of wells is filled withthe particles.
 6. The apparatus of claim 1 wherein the plurality ofpolymer anti-thrombotic conjugate particles serves as a carrier for atherapeutic agent.
 7. The apparatus of claim 1 wherein the plurality ofparticles comprises micro-particles.
 8. The apparatus of claim 1 whereinthe plurality of particles comprises nano-particles.
 9. The apparatus ofclaim 1 further comprising an anti-thrombotic coating applied to thesurface of the frame.